Maintenance of immune homeostasis is crucial for survival. In addition to providing effective clearance of pathogens, a carefully balanced immune system must also limit autoimmunity by preventing responses against self-antigens. The recent characterization of T-regulatory (Treg) cells has revealed a major regulatory pathway that is utilized to prevent inappropriate activation of the immune system and maintain homeostasis. T-regulatory cells arise either during thymic development (tTregs), or are generated in the periphery from effector cells exposed to particular cytokine milieu (induced T-regs or iTregs). It is now well established that al Tregs are characterized by the expression of the transcription factor Foxp3, which orchestrates the production of genes that help mediate the effector functions of these cells. Recent work in our laboratory has revealed that the protein kinase PDK1 and the transcription factor NF-?B play a critical role in Treg development and function. In extensive preliminary studies we have now demonstrated a clear involvement of NF-?B as a critical regulator of Treg function. However, exactly how NF-?B influences Treg function remains unclear. In this grant application we will investigate the role of NF-?B in Tregs beyond its role i regulating the expression of Foxp3. In the first aim we will determine whether NF-?B plays a role in Treg differentiation subsequent to FoxP3 expression by deleting NF-?B inducibly. In the second aim, we will characterize the genetic program in Tregs that is controlled by NF-?B. Finally, in the third aim, we will determine which signaling pathway is responsible for activating NF-?B in Tregs, and explore the role of PKC? in this process.